Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
FASEB J. 2010 Dec;24(12):4904-16. doi: 10.1096/fj.10-162438. Epub 2010 Aug 18.
Acetaminophen [N-acetyl-p-aminophenol (APAP)] is the most common antipyretic/analgesic medicine worldwide. If APAP is overdosed, its metabolite, N-acetyl-p-benzo-quinoneimine (NAPQI), causes liver damage. However, epidemiological evidence has associated previous use of therapeutic APAP doses with the risk of chronic obstructive pulmonary disease (COPD) and asthma. The transient receptor potential ankyrin-1 (TRPA1) channel is expressed by peptidergic primary sensory neurons. Because NAPQI, like other TRPA1 activators, is an electrophilic molecule, we hypothesized that APAP, via NAPQI, stimulates TRPA1, thus causing airway neurogenic inflammation. NAPQI selectively excites human recombinant and native (neuroblastoma cells) TRPA1. TRPA1 activation by NAPQI releases proinflammatory neuropeptides (substance P and calcitonin gene-related peptide) from sensory nerve terminals in rodent airways, thereby causing neurogenic edema and neutrophilia. Single or repeated administration of therapeutic (15-60 mg/kg) APAP doses to mice produces detectable levels of NAPQI in the lung, and increases neutrophil numbers, myeloperoxidase activity, and cytokine and chemokine levels in the airways or skin. Inflammatory responses evoked by NAPQI and APAP are abated by TRPA1 antagonism or are absent in TRPA1-deficient mice. This novel pathway, distinguished from the tissue-damaging effect of NAPQI, may contribute to the risk of COPD and asthma associated with therapeutic APAP use.
对乙酰氨基酚[N-乙酰对氨基酚（APAP）]是全球最常用的解热/镇痛药。如果 APAP 过量，其代谢物 N-乙酰对苯醌亚胺（NAPQI）会导致肝损伤。然而，流行病学证据表明，以前使用治疗剂量的 APAP 与慢性阻塞性肺疾病（COPD）和哮喘的风险相关。瞬时受体电位锚蛋白-1（TRPA1）通道由肽能初级感觉神经元表达。由于 NAPQI 与其他 TRPA1 激活剂一样，是一种亲电分子，我们假设 APAP 通过 NAPQI 刺激 TRPA1，从而导致气道神经源性炎症。NAPQI 选择性地兴奋人重组和天然（神经母细胞瘤细胞）TRPA1。NAPQI 激活 TRPA1 从啮齿动物气道中的感觉神经末梢释放促炎神经肽（P 物质和降钙素基因相关肽），从而导致神经源性水肿和嗜中性粒细胞增多。单次或重复给予治疗（15-60mg/kg）APAP 剂量可在肺部产生可检测水平的 NAPQI，并增加气道或皮肤中的中性粒细胞数量、髓过氧化物酶活性以及细胞因子和趋化因子水平。TRPA1 拮抗作用可减轻 NAPQI 和 APAP 引起的炎症反应，或在 TRPA1 缺陷小鼠中不存在。与 NAPQI 的组织损伤作用不同，这种新途径可能与治疗性 APAP 使用相关的 COPD 和哮喘风险相关。
